1. Definition of Immunodeficient Mice
 

Immunodeficient mice refer to mice with compromised immune function, resulting from congenital genetic defects or deliberate artificial methods. They serve as essential tools for modern medical research. Humanized immunodeficient mice specifically refer to mice carrying human functional genes, cells, or tissues.

The establishment of humanized mouse models provides new options for studying human diseases. These models typically serve as in vivo surrogate systems for investigating human diseases, offering significant advantages and broad application prospects in elucidating pathogenesis mechanisms and drug screening.

 

2. Development of Immunodeficient Mice
 

In the 1960s, the immunodeficient nature of Nude mice was first confirmed. This condition results from Foxn1 gene mutations causing abnormal thymic epithelial cell development, leading to hairlessness and significantly reduced immunity (lack of T cells in the blood). However, natural killer (NK) cell activity is enhanced, and humoral immunity remains normal. The inability to transplant human hematopoietic stem cells remains a limiting factor for the widespread application of this model.

In the 1980s, it was first discovered that human peripheral blood mononuclear cells (PBMCs) could be engrafted in CB17 strain mice, establishing the CB17-SCID (Severe Combined Immunodeficiency) mouse strain. This marked the first stage in the development of humanized mouse models. However, this strain lacks mature B and T cells, and NK cell activity and innate immunity remain high, preventing the transplantation of human hematopoietic stem cells. Consequently, it remains challenging to serve as an optimal humanized mouse model.

In the 1990s, the NOD (Non-Obese Diabetic)-SCID strain, generated through hybridization, better supported the engraftment and growth of human PBMCs or hematopoietic stem cells. This strain exhibits defects in the innate immune system and suppressed NK cell activity, making it the most widely used SCID mouse in recent years and representing the second stage of humanized mouse model development. However, its short lifespan and residual NK cell activity limit its widespread application as a humanized animal model.

In the early 21st century, the NOG and NSG mouse strains, created through targeted mutations of the interleukin-2 receptor gamma chain (IL-2Rγ), represent the third stage of humanized mouse model development. These strains exhibit severely compromised NK cell, T cell, and B cell functions, making them more suitable for constructing humanized mouse models. Their application areas include oncology, hematological diseases, and infectious diseases.

 

3. Applications of Immunodeficient Mice
 

Due to their lack of normal immune function, immunodeficient mice are more susceptible to infections, tumor formation, and accept foreign grafts to a greater extent. Therefore, they are crucial tools for modern medical development. Research applications include:

In Oncology Research: Establishing tumor models in animals facilitates the exploration of tumor pathogenesis mechanisms, evaluation of drug efficacy and safety, and elucidation of drug mechanisms of action. Different mouse backgrounds are suitable for various tumor studies:

● BALB/c nude mice exhibit no rejection of transplanted human tumor cells or tumor tissues, are prone to tumor formation, have high success rates, and low experimental costs, making them the most widely used immunodeficient mouse model currently.

● SCID mice are used to establish human tumor models, with higher engraftment rates for human tumor cells compared to nude mice and higher metastasis rates for malignant tumors, making them suitable for exploring tumor metastasis and proliferation.

● NOD/SCID mice have high tumor formation rates and can be used to construct models for studying human NK cell development and function.

● NOG, NSG, NCG, and NPG mice have high tumor formation rates and are suitable for establishing human tumor xenografts, reconstructing human immune systems, and studying immune responses to tumor immunotherapy or chemotherapy drugs.

 

In Infectious Disease Research: Infectious diseases are caused by pathogenic microorganisms, but pathogens of many genetic diseases such as acquired immunodeficiency syndrome, malaria, and filariasis do not infect mice and other animals, limiting in vivo studies through animal models. The emergence of humanized mouse models provides an effective platform for studying these diseases and conducting vaccine testing. By transplanting human hematopoietic progenitor cells and/or peripheral blood cell suspensions (with surrounding tissues supporting human immune cell growth) into immunodeficient mice, Human Immune System (HIS) mice can be obtained. As the only animal model that can be infected with Human Immunodeficiency Virus (HIV), these mice can be used to test antiviral compounds. Since the mouse immune system can resist hepatitis virus invasion, most mice cannot manifest infectious liver diseases, limiting the development of traditional humanized liver-mouse chimeric models. The AFC8 mouse model has a functional human immune system. After injection of CD34+ HSCs and hepatic progenitor cells (Hep) extracted from human fetal liver tissue, the AFC8-hu HSC/Hep mouse model is formed. Its greatest advantage is that the mouse liver can be infected with hepatitis C virus and generate T cell responses against hepatitis C virus, making it an excellent model for studying the entire process of in vivo infection with hepatitis B and C viruses leading to liver fibrosis.

 

In Leukemia Research: Since the proliferation and differentiation of leukemia cells in immunodeficient mouse-human leukemia models are regulated similarly to the bone marrow microenvironment, they provide unique conditions for studying leukemia proliferation, differentiation, and regulatory mechanisms. Immunodeficient mouse models can also detect the growth and dissemination capacity of leukemia cells and evaluate drugs known to kill or induce apoptosis of leukemia cells in vitro, making them important methods for determining patient prognosis and exploring new leukemia treatment strategies.

 

In Gout Research: Gout is a common metabolic disease caused by widespread deposition of sodium urate crystals in and around joints, leading to acute and chronic non-infectious inflammatory reactions. Due to gene mutations during human evolution, the urate oxidase gene has been inactivated, which is an important reason why humans are prone to gout. Experimental animals, including mice, primarily rely on urate oxidase for uric acid metabolism. Therefore, humans and mice differ significantly in uric acid metabolism and excretion. Experimental conclusions obtained using ordinary mouse models differ from actual human conditions. Evidence shows that after urate oxidase gene knockout, mice can develop hyperuricemia and gout symptoms, becoming a spontaneous hyperuricemia and gout mouse model very similar to human gout pathogenesis. Implanting human joint synovium into the backs of SCID mice with knocked-out urate oxidase genes and injecting human immune cells into these mice will create a humanized mouse model more consistent with human gout pathogenesis characteristics. Gout humanized mouse models have broad application prospects in studying gout pathogenesis mechanisms and drug screening.

 

References:

[1] Kong Weibo, Xu Jingwen. Application of immunodeficient mouse models in tumor therapy research. Pharmacy Today, 2023, 33(3): 186-190.

[2] An Lingbo, Zhang Maosen, Luan Jing. Research progress in humanized mouse models. Chinese Journal of Immunology, 2022, 38(22): 2809-2816.

[3] Zhang Rujun, Li Dongming. Research progress in immunodeficient mouse models. Medicine and Health: Clinical Research, 2017, (2): 56-57.

 

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